Rheumatoid arthritis (RA) is an inflammatory disease associated with intense angiogenesis. The outcome of angiogenesis highly depends on the balance between activity of pro-angiogenic and anti-angiogenic factors. New improved methods for preventing and treating RA and other diseases that are associated with angiogenesis require an understanding of factors that regulate this balance. Recent discovery by our laboratory demonstrates that cadherin-5 (also called VE-cadherin) and VEGFR-1 (one of the receptors for VEGF) have the potential to inhibit vascular endothelial growth factor receptor-2 (VEGFR-2) mediated endothelial cell proliferation, the most well-characterized receptor in angiogenesis. These findings suggest a central role for cadherin-5 and VEGFR-1 in regulating angiogenesis. The central hypothesis of this proposal is that vascular endothelial growth factor (VEGF) is responsible for angiogenesis of RA and that Cadherin-5 and VEGFR-1 may act as an anti-angiogenic factors in this process. To test this hypothesis the following specific aims are proposed.